WO2004037790A1 - Process for the preparation of aryl-piridyl compounds - Google Patents

Process for the preparation of aryl-piridyl compounds Download PDF

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Publication number
WO2004037790A1
WO2004037790A1 PCT/IT2002/000625 IT0200625W WO2004037790A1 WO 2004037790 A1 WO2004037790 A1 WO 2004037790A1 IT 0200625 W IT0200625 W IT 0200625W WO 2004037790 A1 WO2004037790 A1 WO 2004037790A1
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moles
alkyl
compound
phosphines
aryl
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PCT/IT2002/000625
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French (fr)
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Claudio Giordano
Luca Giannini
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Euticals Prime European Therapeuticals Spa
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Priority to US10/530,080 priority Critical patent/US8519144B2/en
Priority to AU2002349814A priority patent/AU2002349814A1/en
Priority to PCT/IT2002/000625 priority patent/WO2004037790A1/en
Priority to EP02785893A priority patent/EP1546106A1/en
Publication of WO2004037790A1 publication Critical patent/WO2004037790A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/51—Acetal radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/48—Aldehydo radicals

Definitions

  • Ri, R 2 , R 3 , * which are the same as one another or different, represent hydrogen, a linear and/or branched Ct-C . alkyl, and/or an aryl, and/or a heteroaryl, or Ri and R 2 and/or R 3 and R., taken together, form a C3-C8 ring, an aryl and/ or a heteroaryl,
  • A represents -COR5, where R5 represents hydrogen, a linear and/ or branched C ⁇ -C alkyl, and/ or an aryl, and/or a heteroaryl, or • A represents -CRs(OR6)(OR 7 ) where R5 has the meaning described above and R ⁇ and R 7 , which are the same as one another or different, represent a linear and/ or branched C ⁇ -C alkyl, and/ or an aryl, and/ or a heteroaryl, or Re and R 7 , joined together, represent a Ci-Cs alkyl or alkenyl.
  • Aryl pyridines are commonly used in organic synthesis as intermediates for the preparation of compounds of various types.
  • 4-(2'-pyridyl)benzaldehyde is an intermediate useful for the preparation of antiviral drugs and, in particular, of drugs effective in the treatment of AIDS, such as, for example, the heterocyclic azahexane derivatives described in International patent application WO 97/40029, which is incorporated herein by reference; amongst the antiviral drugs in question, for example, BMS-232632 (Drugs of the Future 1999, 24(4):375) are noteworthy.
  • Aryl pyridines can be prepared by aryl-aryl cross-coupling reactions (Lohse et al.: S nktt, 1999, Vol. 1; 45-48; Ei-ichi Negishi et al. Heterocycles 1982, Vol. 18 117- 122). Generally, the pyridine derivative carries the leaving group and the aryl derivative is the metallo-organic reagent.
  • the pyridine is hardly ever present in Grignard form, but is present as a boron derivative.
  • An example in which it is shown that a pyridine Grignard does not give an effective cross-coupling reaction is reported in the literature (Kumada, M. et al Tetrahedron 1982, 38, 3347-3354).
  • 4-(2'-pyridyl)benzaldehyde is normally prepared from 4- bromobenzaldehyde and 2-bromopyri.dine (Bold et al.; ].Med.Chem. 1998, 41, 3387 and Drugs of the Future, 1999, 24(4):375).
  • the method provides for the conversion of the bromobenzaldehyde into the corresponding acetal and then into the Grignard reagent BrMgC 6 H CH(OR) 2 ; the Grignard reagent is then reacted with 2- bromopyridine in the presence of NiCl 2 and of l,3-bis(diphenylphosphino)propane (Jnorg.Chem. 1966, 1968) to give 4-(2'-pyridyl)- benzaldehyde as a result of the conversion of the acetal function into aldehyde by treatment in an acid aqueous medium.
  • this method has the great disadvantage of poor repeatability, which is worse, the smaller the quantity of catalyst used.
  • Patent appUcation EP 0,972,765 claims a method for the synthesis of aryl-pyridine based on the use of catalysts based on ferrocenyl phosphines and palladium, starting with halogeno-pyridine and aryl Grignards.
  • International patent appUcation WO 01/27083 describes the preparation of aryl- pyridine compounds in which a pyridyl haUde is reacted with an aryl-magnesium haUde in the presence of a catalytic quantity of a zinc salt and of a catalytic quantity of palladium.
  • the aim of the work which led to the present invention was to find a novel and reUable aryl-aryl cross-coupling method capable of leading to the formation of aryl pyridine from pyridine Grignards or from pyridyl-zinc derivatives, with reproducible and industrially satisfactory yields even in the presence of very smaU quantities of catalyst, eliminating or at least mmimizi ⁇ g the risk of competitive reactions resulting from the presence of alkyl haUdes in the reaction medium.
  • Y represents Cl, Br, I or acetoxy
  • Z represents I, Br, Cl, triflate, sulphonate, phosphate
  • Ri, R 2 , R3, R 4 which are the same as one another or different, represent hydrogen, a Unear and/or branched C ⁇ -C alkyl, and/ or an aryl, and/ or a heteroaryl, or Ri and R 2 and/ or R3 and R4, taken together, form a C3-C8 ring, an aryl and/or a heteroaryl,
  • A represents -COR5, where R5 represents hydrogen, a Unear and/ or branched C ⁇ -C alkyl, and/ or an aryl, and/ or a heteroaryl, or
  • A represents -CRs(OR6)(OR7) where R5 has the meaning described above and Re and R 7 , which are the same as one another or different, represent a linear and/ or branched C ⁇ -C alkyl, and/or an aryl, and/or a heteroaryl, or Re and R 7 , joined together, represent a Ci-C ⁇ alkyl or alkenyl (for example, if a carbonyl function is protected as cycUc ketal).
  • Palladium and nickel are normaUy used in quantities of 0.01-10 moles, preferably 0.05-2 moles, per 100 moles of compound 2; the reaction is carried out by adding an organic solution of compound 2 to an organic solution containing compound 3 and the catalytic system.
  • the organic solvent is preferably an ethereal solvent (such as, for example, not to react with the Grignard compounds) such as THF, 1,2 dimethoxyethane, and/or 1,1- diethoxymethane or a mixture of solvents such as THF/toluene; the reaction is carried out at a temperature of between 20 and 100°C, preferably between 40 and 80°C.
  • an ethereal solvent such as, for example, not to react with the Grignard compounds
  • THF 1,2 dimethoxyethane
  • 1,1- diethoxymethane or a mixture of solvents such as THF/toluene
  • the reaction yield can be increased by operating in the presence of phosphines and/or phosphites, to be used preferably in a molar ratio of catalyst:phosphine/phosphite of between 1:1 and 1:6.
  • the phosphines usable for the purposes of the present invention may be: triaryl phosphines, such as triphenyl phosphine, tritolyl phosphine, trixylyl phosphine, tri-2-furyl phosphine; diaryl alkylphosphines, such as methyldiphenyl phosphine, benzyldiphenyl phosphi ⁇ e, cyclohexyldiphenyl phosphine; dialkylaryl phosphines, such as 2-(di-t- butylphosphi ⁇ o)- biphenyl, 2-(dicyclohexylphosphino)biphenyl; trialkyl phos
  • PaUadium is generaUy added to the reaction medium in the form of complexes with phosphines such as, for example, paUadium tetrakistriphenyl phosphine (Pd(PPh3) ) or as paUadium salt, generaUy acetate or chloride, and a phosphine, preferably triphenyl phosphine; normaUy, one mole of paUadium acetate or chloride is used in combination with 4 moles of triphenyl phosphine (Pd(OAc) 2 or PdCl 2 + 4PPh 3 ).
  • phosphines such as, for example, paUadium tetrakistriphenyl phosphine (Pd(PPh3) ) or as paUadium salt, generaUy acetate or chloride, and a phosphine, preferably triphenyl phosphine; normaUy, one mole of paUadium a
  • nickel is normaUy used in the form of complexes with phosphines, preferably bidentate phosphines, such as, for example, 1,3- bis(diphenylphosphino)propane (dppp) or l,4-bis(diphenylphosphino)butane (dppb); these complexes are added to the reaction solution as salts such as, for example, Ni(dppp)C or Ni(dppb)Cl 2 .
  • phosphines preferably bidentate phosphines, such as, for example, 1,3- bis(diphenylphosphino)propane (dppp) or l,4-bis(diphenylphosphino)butane (dppb); these complexes are added to the reaction solution as salts such as, for example, Ni(dppp)C or Ni(dppb)Cl 2 .
  • the reaction may also be carried out in the presence of zinc salts such as, for example, zinc chloride (ZnCl 2 ), zinc bromide (ZnBr 2 ) and zinc acetate (Zn(OAc) 2 );
  • zinc salts such as, for example, zinc chloride (ZnCl 2 ), zinc bromide (ZnBr 2 ) and zinc acetate (Zn(OAc) 2 );
  • the zinc salt is normaUy used in quantities of 25-120 moles, preferably 35-70 moles, per 100 moles of compound 2.
  • the reaction according to the present invention may also be carried out both in the presence of alkyl haUdes (up to quantities greater than that which is equimolar with the Grignard), and in the presence of variable quantities of alkyl Grignard.
  • This aspect is very important from an appUcational point of view, since the preparations of pyridyl Grignards known in the Uterature (Tetrahedron 2000, 56, 1349 or in JOC 1959, 24, 504 and Red Trap. Chim. Pays Bas 1965, 84, 439) lead to solutions containing alkyl hahdes or alkyl-magnesium haUdes in variable quantities. It is therefore possible to use the organic solutions of the pyridyl Grignard selected, without further purification.
  • the compound of formula 2 is produced by reaction of the corresponding halogeno(bromo, iodo)- pyridine with a catalytic quantity of alkyl haUde in the presence of an at least stoichiometric quantity of magnesium;
  • the alkyl haUde is normaUy a Ci-Cs alkyl chloride or bromide, preferably ethyl bromide or isopropyl bromide or chloride.
  • 100 moles of halogeno-pyridine are reacted with 10-20 moles of alkyl haUde and 100-120 moles of magnesium.
  • the reaction is generaUy carried out at a temperature of 0-60°C, preferably at 15-35°C, in an aprotic organic solvent which does not react with a Grignard reagent, preferably in tetrahydrofuran or mixtures of tetrahydrofuran and toluene; the solution thus obtained is then added dropwise to the solution containing compound 3 and the catalytic system.
  • a Grignard reagent preferably in tetrahydrofuran or mixtures of tetrahydrofuran and toluene
  • the reaction mixture was kept at 50°C for 30 minutes and then cooled to 20-25°C.
  • Example 1 was repeated with the use of a different quantity of anhydrous zinc chloride (7.1 g, 52.1 mmoles), producing a 70% yield of 4-(3'-pyridyl)-benzaldehyde- dimethyl acetal, relative to the 4-bromobenzaldehyde dimethyl acetal loaded.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A method is described for the preparation of aryl-pyridine compounds of formula (I) by cross-coupling reaction, promoted by catalytic systems based on palladium or nickel between compounds of formula (II) and (III) in which: - Met represents Mg or Zn, - Y represents C1, Br, I or acetoxy, - Z represents I, Br, Cl, triflate, sulphonate, phosphate, - Rl, R2, R3, R4, which are the same as one another or different, represent hydrogen, a linear and/or branched Cl-C4 alkyl, and/or an aryl, and/or a heteroaryl, or Rl and R2 and/or R3and R4, taken together, form a C3-C8 ring, an aryl and/or a heteroaryl, - A represents -COR5 where R5 represents hydrogen, a linear and/or branched Cl-C4 alkyl, and/or an aryl, and/or a heteroaryl, or - A represents -CRs5(OR6)(OR7) where R5 has the meaning described above and R6 and R7, which are the same as one another or different, represent a linear and/or branched C1-C4 alkyl, and/or an aryl, and/or a heteroaryl, or R6 and R7, joined together, represent a C1-C8 alkyl or alkenyl.

Description

Process for the preparation of aryl-piridyl compounds
The subject of the present invention is the preparation of compounds of formula 1:
Figure imgf000002_0001
1 from compounds of formula 2 and formula 3.
Figure imgf000002_0002
in which:
• Met represents Mg or Zn,
• Y represents Cl, Br, I or acetoxy,
• Z represents I, Br, Cl, triflate, sulphonate, phosphate,
• Ri, R2, R3, *, which are the same as one another or different, represent hydrogen, a linear and/or branched Ct-C . alkyl, and/or an aryl, and/or a heteroaryl, or Ri and R2 and/or R3 and R., taken together, form a C3-C8 ring, an aryl and/ or a heteroaryl,
• A represents -COR5, where R5 represents hydrogen, a linear and/ or branched Cι-C alkyl, and/ or an aryl, and/or a heteroaryl, or • A represents -CRs(OR6)(OR7) where R5 has the meaning described above and Rό and R7, which are the same as one another or different, represent a linear and/ or branched Cι-C alkyl, and/ or an aryl, and/ or a heteroaryl, or Re and R7, joined together, represent a Ci-Cs alkyl or alkenyl. STATE OF THE ART
Aryl pyridines are commonly used in organic synthesis as intermediates for the preparation of compounds of various types.
4-(2'-pyridyl)benzaldehyde is an intermediate useful for the preparation of antiviral drugs and, in particular, of drugs effective in the treatment of AIDS, such as, for example, the heterocyclic azahexane derivatives described in International patent application WO 97/40029, which is incorporated herein by reference; amongst the antiviral drugs in question, for example, BMS-232632 (Drugs of the Future 1999, 24(4):375) are noteworthy.
Aryl pyridines can be prepared by aryl-aryl cross-coupling reactions (Lohse et al.: S nktt, 1999, Vol. 1; 45-48; Ei-ichi Negishi et al. Heterocycles 1982, Vol. 18 117- 122). Generally, the pyridine derivative carries the leaving group and the aryl derivative is the metallo-organic reagent.
There is a limited number of examples of aryl-aryl cross-coupling in which the pyridine constitutes the organometallic reagent (Kalinin, D.N., Synthesis 1992, 413- 432; Tetrahedron 1998, 54, 263-303).
Moreover, in the known examples of this type, the pyridine is hardly ever present in Grignard form, but is present as a boron derivative. An example in which it is shown that a pyridine Grignard does not give an effective cross-coupling reaction is reported in the literature (Kumada, M. et al Tetrahedron 1982, 38, 3347-3354). In particular, 4-(2'-pyridyl)benzaldehyde is normally prepared from 4- bromobenzaldehyde and 2-bromopyri.dine (Bold et al.; ].Med.Chem. 1998, 41, 3387 and Drugs of the Future, 1999, 24(4):375). The method provides for the conversion of the bromobenzaldehyde into the corresponding acetal and then into the Grignard reagent BrMgC6H CH(OR)2; the Grignard reagent is then reacted with 2- bromopyridine in the presence of NiCl2 and of l,3-bis(diphenylphosphino)propane (Jnorg.Chem. 1966, 1968) to give 4-(2'-pyridyl)- benzaldehyde as a result of the conversion of the acetal function into aldehyde by treatment in an acid aqueous medium. However, this method has the great disadvantage of poor repeatability, which is worse, the smaller the quantity of catalyst used.
Patent appUcation EP 0,972,765, on the other hand, claims a method for the synthesis of aryl-pyridine based on the use of catalysts based on ferrocenyl phosphines and palladium, starting with halogeno-pyridine and aryl Grignards. International patent appUcation WO 01/27083 describes the preparation of aryl- pyridine compounds in which a pyridyl haUde is reacted with an aryl-magnesium haUde in the presence of a catalytic quantity of a zinc salt and of a catalytic quantity of palladium.
The aim of the work which led to the present invention was to find a novel and reUable aryl-aryl cross-coupling method capable of leading to the formation of aryl pyridine from pyridine Grignards or from pyridyl-zinc derivatives, with reproducible and industrially satisfactory yields even in the presence of very smaU quantities of catalyst, eliminating or at least mmimiziαg the risk of competitive reactions resulting from the presence of alkyl haUdes in the reaction medium.
DESCRIPTION OF THE INVENTION It has now surprisingly been found that compounds of formula 1 can be produced with high yields and purity by cross-coupling reaction between compounds of formula 2 and compounds of formula 3, promoted by catalytic systems based on paUadium or nickel, in accordance with the scheme given below.
Figure imgf000004_0001
in which:
• Met represents Mg or Zn,
• Y represents Cl, Br, I or acetoxy, • Z represents I, Br, Cl, triflate, sulphonate, phosphate,
• Ri, R2, R3, R4, which are the same as one another or different, represent hydrogen, a Unear and/or branched Cι-C alkyl, and/ or an aryl, and/ or a heteroaryl, or Ri and R2 and/ or R3 and R4, taken together, form a C3-C8 ring, an aryl and/or a heteroaryl,
• A represents -COR5, where R5 represents hydrogen, a Unear and/ or branched Cι-C alkyl, and/ or an aryl, and/ or a heteroaryl, or
• A represents -CRs(OR6)(OR7) where R5 has the meaning described above and Re and R7, which are the same as one another or different, represent a linear and/ or branched Cι-C alkyl, and/or an aryl, and/or a heteroaryl, or Re and R7, joined together, represent a Ci-Cβ alkyl or alkenyl (for example, if a carbonyl function is protected as cycUc ketal).
Palladium and nickel are normaUy used in quantities of 0.01-10 moles, preferably 0.05-2 moles, per 100 moles of compound 2; the reaction is carried out by adding an organic solution of compound 2 to an organic solution containing compound 3 and the catalytic system.
The organic solvent is preferably an ethereal solvent (such as, for example, not to react with the Grignard compounds) such as THF, 1,2 dimethoxyethane, and/or 1,1- diethoxymethane or a mixture of solvents such as THF/toluene; the reaction is carried out at a temperature of between 20 and 100°C, preferably between 40 and 80°C.
The reaction yield can be increased by operating in the presence of phosphines and/or phosphites, to be used preferably in a molar ratio of catalyst:phosphine/phosphite of between 1:1 and 1:6. The phosphines usable for the purposes of the present invention may be: triaryl phosphines, such as triphenyl phosphine, tritolyl phosphine, trixylyl phosphine, tri-2-furyl phosphine; diaryl alkylphosphines, such as methyldiphenyl phosphine, benzyldiphenyl phosphiαe, cyclohexyldiphenyl phosphine; dialkylaryl phosphines, such as 2-(di-t- butylphosphiαo)- biphenyl, 2-(dicyclohexylphosphino)biphenyl; trialkyl phosphines, such as ttdisopropyl phosphine, tricyclohexyl phosphine, tributyl phosphine, trusobutyl phosphine, di-t-butylmethyl phosphine; bidentate phosphines such as 2- 2'bis(diphenylphosphino)-l, binaphthyl (racemic BINAP), 1,2- bis (dicyclohexylphosphino) ethane, l,l'bis(diphenyl- phosphino)ferrocene (dppf), 1,2- bis(diethylphosphino)- ethane, l,2-bis(dipentafluorophenylphospn__no) ethane, 1,3- bis(<_Hphenylphosphino)propane (dppp), l,4-bis(diphenyl- phosphino)butane (dppb). PaUadium is generaUy added to the reaction medium in the form of complexes with phosphines such as, for example, paUadium tetrakistriphenyl phosphine (Pd(PPh3) ) or as paUadium salt, generaUy acetate or chloride, and a phosphine, preferably triphenyl phosphine; normaUy, one mole of paUadium acetate or chloride is used in combination with 4 moles of triphenyl phosphine (Pd(OAc)2 or PdCl2 + 4PPh3). Similarly, nickel is normaUy used in the form of complexes with phosphines, preferably bidentate phosphines, such as, for example, 1,3- bis(diphenylphosphino)propane (dppp) or l,4-bis(diphenylphosphino)butane (dppb); these complexes are added to the reaction solution as salts such as, for example, Ni(dppp)C or Ni(dppb)Cl2.
OptionaUy, the reaction may also be carried out in the presence of zinc salts such as, for example, zinc chloride (ZnCl2), zinc bromide (ZnBr2) and zinc acetate (Zn(OAc)2); the zinc salt is normaUy used in quantities of 25-120 moles, preferably 35-70 moles, per 100 moles of compound 2. In order for the cross-coupling reaction to proceed with high yields and high selectivity in the presence of a minimum quantity of catalyst, it is preferable to prevent the accumulation of Grignard reagents in the reaction medium and they should therefore be in a dynamic deficiency relative to the zinc salt (that is, the Grignard reagent is added dropwise to a solution already containing compound 3, paUadium, phosphine binder, and zinc salt). According to a preferred embodiment of the invention, 0.01-0.1 moles of paUadium and 40-70 moles of zinc are used per 100 moles of compound 2; the molar ratio between paUadium and compound 2 is less than 1:100. Alternatively, in a second embodiment, 0.01-2 moles of nickel per 100 moles of compound 2 are used (that is, in the absence of zinc salts).
The reaction according to the present invention may also be carried out both in the presence of alkyl haUdes (up to quantities greater than that which is equimolar with the Grignard), and in the presence of variable quantities of alkyl Grignard. This aspect is very important from an appUcational point of view, since the preparations of pyridyl Grignards known in the Uterature (Tetrahedron 2000, 56, 1349 or in JOC 1959, 24, 504 and Red Trap. Chim. Pays Bas 1965, 84, 439) lead to solutions containing alkyl hahdes or alkyl-magnesium haUdes in variable quantities. It is therefore possible to use the organic solutions of the pyridyl Grignard selected, without further purification.
According to the preferred embodiment of the present invention, the compound of formula 2 is produced by reaction of the corresponding halogeno(bromo, iodo)- pyridine with a catalytic quantity of alkyl haUde in the presence of an at least stoichiometric quantity of magnesium; the alkyl haUde is normaUy a Ci-Cs alkyl chloride or bromide, preferably ethyl bromide or isopropyl bromide or chloride. Preferably, 100 moles of halogeno-pyridine are reacted with 10-20 moles of alkyl haUde and 100-120 moles of magnesium. The reaction is generaUy carried out at a temperature of 0-60°C, preferably at 15-35°C, in an aprotic organic solvent which does not react with a Grignard reagent, preferably in tetrahydrofuran or mixtures of tetrahydrofuran and toluene; the solution thus obtained is then added dropwise to the solution containing compound 3 and the catalytic system.
These and further aspects of the invention wiU become clear from the foUowing examples which should be considered as illustrative and not limiting thereof.
PREPARATION OF THE GRIGNARD REAGENT EXAMPLE 1 - GRIGNARD A
Ethyl bromide (2.2 g 0.02 moles) was added to a suspension of magnesium (0.29g, 0.12 moles) in anhydrous tetrahydrofuran (58.5 g) kept at 20°C, with stirring, in an inert atmosphere, whilst the internal temperature was kept below 35°C. 3- bromopyridine (16.0 g, 0.101 moles) was added over 3 hours to the solution thus obtained, whilst the temperature was controUed at between 25 and 30°C. Stirring of the reaction mixture was continued at 25°C for a further 3 hours. EXAMPLE 2 - GRIGNARD B
A solution of 2-bromopyridine (16 g, 0.101 moles) in anhydrous tetrahydrofuran (5g) was added over 1 hour to a solution of 2-propyl-magnesium chloride (2M in tetrahydrofuran, 50.6 ml, Aldrich cat. 2000/2001) kept at 25°C. Stirring of the mixture was continued at 25°C for 4 hours. EXAMPLE 3 - GRIGNARD C A solution of 2-ρropyl-magnesium chloride (2M i tetrahydrofuran, 51 g, 50.6 ml,
Aldrich cat. 2000/2001) was added over 1 hour to a solution of 2-bromopyrid__ne (16 g, 0.101 moles) in anhydrous tetrahydrofuran (13g), kept at 25°C. Stirring of the mixture was continued at 25°C for 4 hours.
EXAMPLE 4 - GRIGNARD D
A solution of 2-propyl-magnesium chloride (2M in tetrahydrofuran, 9,8 g 0.02 moles,
Aldrich cat. 2000/2001) was added to a suspension of magnesium (1.96 g, 0.08 moles) in anhydrous tetrahydrofuran (53.2 g), kept at 20°C, with stirring, in an inert atmosphere. 2-bromopyridine (16.0 g 0.101 moles) was then added over 3 hours whUst the temperature was controUed at between 25 and 30°C. Stirring of the reaction mixture was continued at 25°C for 3 hours.
COUPLING REACTION
EXAMPLE 5 - Preparation of 4-(3'-pyridyl)benzaldehyde
4-bromobenzaldehyde dimethyl acetal (9.5 g, 41.1 mmoles) and paUadium tetrakistriphenyl phosphine (50 mg, 0.04 mmoles) were added to a mixture of anhydrous zinc chloride (2.1 g 15.4 mmoles) in anhydrous tetrahydrofuran (23 g), with stirring, in an inert atmosphere. A solution of Grignard A (40.3 g) was added over 4 hours to the resulting mixture, which was kept at 50°C with stirring, in an inert atmosphere.
The reaction mixture was kept at 50°C for 30 minutes and then cooled to 20-25°C.
An 85% yield of 4-(3'-pyridyl)- benzaldehyde-dimethyl acetal, relative to the 4- bromobenzaldehyde dimethyl acetal loaded, was obtained. After acid hydrolysis, an
85% yield of 4-(3'-pyridyl)- benzaldehyde was obtained.
EXAMPLE 6 - Preparation of 4-(3'-pyridyl)benzaldehyde
Example 1 was repeated with the use of a different quantity of anhydrous zinc chloride (7.1 g, 52.1 mmoles), producing a 70% yield of 4-(3'-pyridyl)-benzaldehyde- dimethyl acetal, relative to the 4-bromobenzaldehyde dimethyl acetal loaded.
EXAMPLE 7 - Preparation of 4-(2'-pyridyl)benzaldehyde
4-bromobenzaldehyde dimethyl acetal (9.5 g, 41.1 mmoles) and paUadium tetrakistriphenyl phosphine (0.1 g, 0.087 mmoles) were added to a mixture of anhydrous zinc chloride (2.1 g, 15.4 mmoles) in tetrahydrofuran (23 g), with stirring in an inert atmosphere. A solution of Grignard C (41.9 g) was added over 6 hours to the resulting mixture, which was kept at 50°C with stirring, in an inert atmosphere. The reaction mixture was kept at 50°C for 30 minutes and then cooled to 20-25°C. A 64% yield of 4-(2'-pyridyl)- benzaldehyde-dimethyl acetal, relative to the 4- bromobenzaldehyde dimethyl acetal loaded, was obtained.

Claims

1. A method for the preparation of compounds of formula 1,
Figure imgf000010_0001
in which a solution containing a compound of formula 2 is added dropwise to a solution containing a compound of formula 3
Figure imgf000010_0002
in which:
• Met represents Mg or Zn,
• Y represents Cl, Br, I or acetoxy,
• Z represents I, Br, Cl, triflate, sulphonate, phosphate,
• Ri, R2, R3, R_t, which are the same as one another or different, represent hydrogen, a linear and/or branched Cι-C alkyl, and/ or an aryl, and/ or a heteroaryl, or Ri and R2 and/or R3 and R-t, taken together, form a C3-C8 ring, an aryl and/or a heteroaryl, • A represents -COR5, where R5 represents hydrogen, a linear and/ or branched Cι-C alkyl, and/ or an aryl, and/ or a heteroaryl, or
• A represents -CRs(OR6)(OR7) where R5 has the meaning described above and Re and R7, which are the same as one another or different, represent a Unear and/ or branched Cι-C alkyl, and/or an aryl, and/or a heteroaryl, or Re and R7, joined together, represent a Cι-C8 alkyl or alkenyl, in the presence of catalytic systems based on paUadium or nickel.
2. A method according to Claim 1, characterized in that compound 2 is prepared by reaction of the corresponding halogeno-pyridine with a catalytic quantity of alkyl haUde, in the presence of an at least stoichiometric quantity of magnesium.
3. A method according to Claim 2, characterized in that 100 moles of the halogeno- pyridine are reacted with 10-20 moles of alkyl haUde and 100-120 moles of magnesium.
4. A method according to Claim 2, characterized in that the alkyl haUde is a O-Cs alkyl chloride or bromide.
5. A method according to Claim 4, characterized in that the alkyl haUde is ethyl bromide or isopropyl bromide or chloride.
6. A method according to Claim 1, characterized in that compound 2 is prepared by reaction of the corresponding halogeno-pyridine with an at least stoichiometric quantity of an alkyl-magnesium haUde.
7. A method according to Claim 6, characterized in that the alkyl-magnesium halide is a chloride or a bromide of a Cι-C8 alkyl-magnesium salt, preferably an ethyl or isopropyl magnesium salt.
8. A method according to Claim 1, characterized in that the paUadium and/ or the nickel are used in quantities of 0.01-10 moles, preferably 0.05-2 moles, per 100 moles of compound 2.
9. A method according to Claim 1, characterized in that the solvent is an ethereal solvent, preferably THF, 1,2 dimethoxy ethane, and/ or 1, -diethoxymethane, or a THF/toluene mixture.
10. A method according to Claim 1, characterized in that it is performed at a temperature of between 20 and 100°C, preferably between 40 and 80°C.
11. A method according to Claim 1, characterized in that it is performed in the presence of phosphines and/ or phosphites.
12. A method according to Claim 11, characterized in that the phosphines and/or phosphites are used in a molar ratio of metal:phosphine/phosphite of between 1:1 and 1:6.
13. A method according to Claim 11, characterized in that the phosphines are selected from triaryl phosphines, diarylalkyl phosphines, trialkyl phosphines, and bidentate phosphines.
14. A method according to Claim 11, characterized in that paUadium is used in the form of complexes with phosphines, preferably as Pd(PPli3) .
15. A method according to Claim 11, characterized in that paUadium is used in the salt form, generaUy in acetate or chloride form, in combination with a phosphine, preferably triphenyl phosphine.
16. A method according to Claim 11, characterized in that nickel is used in the form of complexes with phosphines, preferably bidentate phosphines.
17. A method according to Claim 1, characterized in that it is performed in the presence of zinc salts, preferably ZnCl2, ZnBr or Zn(OAc)2.
18. A method according to Claim 17, characterized in that the zinc salt is used in quantities of 25-120 moles, preferably 35-70 moles, per 100 moles of compound 2.
19. A method according to Claim 18 in which Met is magnesium, characterized in that 0.01-0.1 moles of palladium and 40-70 moles of zinc are used per 100 moles of compound 2.
20. A method according to Claim 17, characterized in that the molar ratio between palladium and compound 2 is less than 1:100.
21. A method according to Claim 1, characterized in that compound 2 is used in a dynamic deficiency relative to the zinc salt.
22. A method according to Claim 1, characterized in that 0.5-1.2 moles, preferably 1 mole, of compound 2 is used per 1 mole of compound 3.
23. A method for the preparation of heterocycUc azahexane derivatives with antiviral action, characterized in that it comprises a method according to Claims 1-22.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
EP0972765A1 (en) * 1998-07-11 2000-01-19 Clariant GmbH Process for preparing arylpyridines
WO2001027083A1 (en) * 1999-10-12 2001-04-19 Euticals Prime European Therapeutical Spa Process for the preparation of aryl-pyridinyl compounds

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Publication number Priority date Publication date Assignee Title
TW409125B (en) 1996-04-22 2000-10-21 Novartis Ag Antivirally active heterocyclic azahexane derivatives

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EP0972765A1 (en) * 1998-07-11 2000-01-19 Clariant GmbH Process for preparing arylpyridines
WO2001027083A1 (en) * 1999-10-12 2001-04-19 Euticals Prime European Therapeutical Spa Process for the preparation of aryl-pyridinyl compounds

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